U.S. patent number 5,229,385 [Application Number 07/818,856] was granted by the patent office on 1993-07-20 for quinone derivatives, their production and use.
This patent grant is currently assigned to Takeda Chemical Industries, Ltd.. Invention is credited to Kohei Nishikawa, Shinji Terao.
United States Patent |
5,229,385 |
Terao , et al. |
July 20, 1993 |
**Please see images for:
( Certificate of Correction ) ** |
Quinone derivatives, their production and use
Abstract
Quinone derivatives represented by the general formula ##STR1##
(wherein, R.sup.1 and R.sup.2, the same or different, refer to
hydrogen atom, methyl or methoxymethyl group, or R.sup.1 and
R.sup.2 bind together to form --CH.dbd.CH--CH.dbd.CH--; R.sup.3 is
hydrogen atom or methyl group; R.sup.4 is nitrogen-containing
heterocyclic group which may be substituted; R.sup.5 is hydrogen
atom, methyl group, hydroxymethyl group which may be substituted,
or carboxyl group which may be esterified or amidated; Z is
##STR2## (wherein, R' is hydrogen atom or methyl group); n is an
integer from 0 through 12, m is an integer from 0 through 3, and k
is an integer from 0 through 7, providing that, when m is 2 or 3, Z
and k are able to vary appropriately in the repeating unit shown in
[]), and the hydroquinone derivatives thereof, are novel compounds,
possess improvement effects of metabolism of poly unsaturated fatty
acids, particularly two or more of inhibition of production of
fatty acid peroxides, inhibition of production of metabolites in
5-lipoxygenase pathway, inhibition of thromboxane A.sub.2
synthetase, thromboxane A.sub.2 receptor antagonism and scavenging
action of active oxygen species, and of use as drugs, such as
antithrombotics, anti-vascular constriction agents, anti-asthma
agent, antiallergic agents, therpeutics for psoriasis, agents for
improvement in heart, brain and cardiovascular systems,
therapeutics for nephritis, active oxygen-eliminating agents,
anticancer agents, agents for improvement of control of
arachidonate cascade products, etc.
Inventors: |
Terao; Shinji (Osaka,
JP), Nishikawa; Kohei (Kyoto, JP) |
Assignee: |
Takeda Chemical Industries,
Ltd. (Osaka, JP)
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Family
ID: |
27548867 |
Appl.
No.: |
07/818,856 |
Filed: |
January 10, 1992 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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600149 |
Oct 19, 1990 |
5106858 |
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343142 |
Apr 25, 1989 |
4985447 |
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4138 |
Jan 16, 1987 |
4851413 |
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Foreign Application Priority Data
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Jan 30, 1986 [JP] |
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61-19547 |
Apr 23, 1986 [JP] |
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61-94168 |
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Current U.S.
Class: |
514/235.5;
514/236.8; 514/326; 514/342; 514/397; 514/399; 544/111; 546/191;
546/208; 546/209; 546/280.4; 548/204; 548/205; 548/336.1;
548/336.5; 548/341.1; 548/341.5 |
Current CPC
Class: |
C07D
213/50 (20130101); C07D 213/55 (20130101); C07D
409/06 (20130101); C07D 233/56 (20130101); C07D
249/08 (20130101); C07D 231/12 (20130101) |
Current International
Class: |
C07D
409/06 (20060101); C07D 213/00 (20060101); C07D
521/00 (20060101); C07D 213/50 (20060101); C07D
213/55 (20060101); C07D 409/00 (20060101); C07D
277/30 (); C07D 201/20 (); A01N 043/78 (); A61K
031/535 () |
Field of
Search: |
;548/204,205,336.1,336.5,341.1,341.5,191,208,209,280
;514/365,397,399,235.5,236.8,326,342 ;546/191,208,209,280
;544/111 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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0003560 |
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Aug 1979 |
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EP |
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0004727 |
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Oct 1979 |
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EP |
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0092136 |
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Oct 1983 |
|
EP |
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0171251 |
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Feb 1986 |
|
EP |
|
Other References
Hori et al., Chem. Abstracts, vol. 93, No. 25 (1980), p. 810,
Abstract No. 238974r. .
Cameron et al., Aust. J. Chem. (1976), vol. 29, pp. 1163-1165.
.
Kort et al., J. Chem. Soc. (C) 1966) pp. 2190-2196. .
Furukawa et al., Chem. Abstr. vol. 84, No. 11 (1976) Abstract No.
74280x. .
Babichev et al., Chem. Abstr., vol. 70, No. 25, p. 339, Abstract
No. 115062j (1976). .
Takada et al., Chem. Abstr., vol. 75, No. 9 (1971) p. 432 Abstract
No. 63546b. .
Cameron et al., Journ. Chem. Soc. (C) 1969, pp. 1245-1251..
|
Primary Examiner: Ivy; C. Warren
Assistant Examiner: Covington; Raymond
Attorney, Agent or Firm: Wenderoth, Lind & Ponack
Parent Case Text
This application is a division of application Ser. No. 07/600,149,
filed Oct. 19, 1990 (now U.S. Pat. No. 5,106,858) which is a
division of Ser. No. 07/343,142, filed Apr. 25, 1989 (now U.S. Pat.
No. 4,985,447) which is a division of application Ser. No.
07/004,138, filed Jan. 16, 1987 (now U.S. Pat. No. 4,851,413).
Claims
What is claimed is:
1. A compound of the formula: ##STR29## R.sup.1 and R.sup.2 are the
same or different and are methyl or methoxy, or
R.sup.1 and R.sup.2 bind together to form
--CH.dbd.CH--CH.dbd.CH--;
R.sup.3 is methyl
R.sup.4 is thiazolyl or imidazolyl which may be substituted by 1 to
3 substituents selected from the group consisting of alkyl of 1 to
3 carbon atoms, phenyl, p-tolyl, m-tolyl, pyridyl and
3-pyridylmethyl;
R.sup.5 is hydrogen, methyl, hydroxymethyl, methoxymethyl,
acetoxymethyl, nitroxymethyl, carbamoyloxymethyl or a carboxyl
group which may be esterified with an alkyl having 1 to 3 carbon
atoms or amidated to form hydroxyaminocarbonyl, morpholinocarbonyl,
piperidinocarbonyl or carboxamide of the formula: ##STR30## wherein
R.sup.11 and R.sup.12 individually represent hydrogen, C.sub.1
-C.sub.7 alkyl, phenyl hydroxyl, methoxy or chlorine or
naphthyl,
n is 0 or an integer from 1 through 12;
m is 0 or an integer from 1 through 3;
k is 0 or an integer from 1 through 7
Z is ##STR31## wherein R' is hydrogen or methyl, providing that,
when m is 2 or 3, k may vary appropriately in the repeating unit
shown in [].
2. A compound as claimed in claim 1, wherein m is 0 or 1.
3. A compound as claimed in claim 1, wherein m is 1 and k is 0 or
an integer from 1 through 3.
4. A compound as claimed in claim 1, wherein R.sup.4 is imidazolyl
which may be substituted by 1 to 3 substituents selected from the
group consisting of alkyl of 1 to 3 carbon atoms, phenyl, p-tolyl,
m-tolyl, pyridyl and 3-pyridylmethyl.
5. A compound as claimed in claim 1, wherein R.sup.1 and R.sup.2 is
methyl or R.sup.1 and R.sup.2 bind together to form
--CH.dbd.CH--CH.dbd.CH--.
6. A compound as claimed in claim 1, wherein R.sup.5 is
hydroxymethyl, methoxymethyl, acetoxymethyl, nitroxymethyl or
carbamoyloxymethyl.
7. A compound as claimed in claim 1, wherein R.sup.5 is a carboxyl
group which may be esterified or amidated.
8. A compound as claimed in claim 7, wherein the carboxyl group
which may be esterified or amidated is carboxyl, an alkoxycarbonyl
wherein the alkyl has 1 to 3 carbon atoms, aminocarbonyl, a mono-
or di-alkylaminocarbonyl wherein the alkyl has 1 to 3 carbon atoms,
phenylaminocarbonyl, diphenylaminocarbonyl.
9. A compound as claimed in claim 1, wherein the compound is
2-[(1-imidazolyl)methyl]-3,5,6-trimethyl-1,4-benzoquinone
hydrochloride.
10. A pharmaceutical composition for the treatment of disease due
to dysfunction of heart, brain, lung or kidney which comprises a
pharmaceutically effective amount of a compound according to claim
1 or the corresponding hydroquinone derivative thereof and
pharmaceutically acceptable carrier therefor.
11. A method for the treatment of a disease due to dysfunction of
heart, brain, lung or kidney which comprises administering to a
mammal a pharmaceutically effective amount of a compound according
to claim 1 or the corresponding hydroquinone derivative thereof.
Description
This invention relates to novel quinone derivatives each of which
exerts two or more effects among thromboxane A.sub.2 synthetase
inhibition, thromboxane A.sub.2 receptor antagonism, 5-lipoxygenase
inhibition and scavenging action of active oxygen species, and is
usuful, based on the composite effects, for treatment and
prevention of diseases due to dysfunction of heart, brain, lung and
kidney. This invention also relates to the method of production of
the said quinone derivatives, and pharmaceutical compositions
containing such derivatives. This invention is useful in the field
of medicine.
PRIOR ART
A number of reports have been published on specific inhibitors,
antagonists, or scavengers for one of thromboxane A.sub.2
(hereinafter abbreviated as TXA.sub.2) synthetase, TXA.sub.2
receptor, 5-lipoxygenase and active oxygen species. However, no
attempt has been made to design a compound having a composite
pharmacological action consisting of two or more effects among
TXA.sub.2 synthetase inhibition, TXA.sub.2 receptor antagonism,
5-lipoxygenase inhibition and scavenging action of active oxygen
species.
This invention offers novel quinone compounds exerting two or more
effects among TXA.sub.2 synthetase inhibition, TXA.sub.2 receptor
antagonism, 5-lipoxygenase inhibition, and scavenging action of
active oxygen species.
This invention relates to
1. Quinone derivatives represented by the general formula ##STR3##
(wherein, R.sup.1 and R.sup.2 which are, the same or different,
refer to a hydrogen atom, methyl or methoxy group, or R.sup.1 and
R.sup.2 bind together to form --CH.dbd.CH--CH.dbd.CH--; R.sup.3 is
a hydrogen atom or methyl group; R.sup.4 is a nitrogen-containing
heterocyclic group which may be substituted; R.sup.5 is a hydrogen
atom, methyl group, hydroxymethyl group which may be substituted,
or carboxyl group which may be esterified or amidated; Z is
##STR4## (wherein, R' is a hydrogen atom or methyl group); n is an
integer from 0 through 12, m is an integer from 0 through 3, and k
is an integer from 0 through 7, providing that, when m is 2 or 3, Z
and k are able to vary appropriately in the repeating unit shown in
[]), and the hydroquinone derivatives thereof,
2. a method of production of quinone derivatives represented by the
general formula (I) characterized by the reaction of a compound
represented by the general formula ##STR5## (wherein, R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, Z, k, m and n are the same as
described above; R.sup.6 is a hydrogen atom, methyl, methoxymethyl,
benzyl, or 2-tetrahydropyranyl group; R.sup.7 is a hydrogen atom,
hydroxyl, methoxy, methoxymethyloxy, benzyloxy, or
2-tetrahydropyranyloxy group) with an oxidant,
3. a method of production of hydroquinone derivatives represented
by the general formula ##STR6## (wherein, the symbols are the same
as described above) characterized by the protective-group
eliminating reaction of a compound having the general formula
##STR7## (wherein, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, Z,
k, m, and n are the same as described above; R.sup.8 is methyl,
methoxymethyl, benzyl, or 2-tetrahydropyranyl), and,
4. pharmaceutical compositions containing, as the active
ingredient, a quinone derivative represented by the general formula
(I) or a hydroquinone derivative thereof.
The nitrogen-containing heterocyclic groups represented by R.sup.4
in the general formula (I) described above include 5- or 6-membered
cyclic groups containing at least one nitrogen atom as the ring
member atom, in the concrete, pyridyl groups (2-pyridyl, 3-pyridyl,
4-pyridyl), thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl),
imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-thiazolyl
and 1-imidazolyl are preferable, and 3-pyridyl is the most
desirable. These nitrogen-containing heterocyclic groups may
contain 1 to 3 substituents at a given position on the ring, and
such substituents include alkyl groups having 1 to 3 carbon atoms
such as methyl and ethyl, phenyl group, p-tolyl group, m-tolyl
group, pyridyl group (2-pyridyl, 3-pyridyl), and 3-pyridylmethyl
group.
The hydroxymethyl group represented by R.sup.5 may be substituted,
including, in addition to the unsubstituted hydroxymethyl group,
methoxymethyl, acetoxymethyl, nitroxymethyl, and
carbamoyloxymethyl; the esterified carboxyl group includes
alkoxycarbonyl groups having 2 to 5 carbons such as
methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, and
butoxycarbonyl. The amidated carboxyl group represented by R.sup.5
may be a substituted aminocarbonyl in which the amino group is
substituted, or a cyclic aminocarbonyl. The substituents for the
amino group in the substituted aminocarbonyl include alkyl having 1
to 4 carbon atoms such as methyl, ethyl, propyl and butyl, aryl
having 6 to 10 carbon atoms such as phenyl and naphthyl (which may
be substituted by hydroxyl, amino, nitro, halogen, methyl or
methoxy at a given position of the ring), and the hydroxyl group;
the amidated carboxyl groups are exemplified by aminocarbonyl,
mono- or di-alkylaminocarbonyl having 2 to 4 carbon atoms
(methylaminocarbonyl, ethylaminocarbonyl, isopropylaminocarbonyl,
dimethylaminocarbonyl), phenylaminocarbonyl, substituted
phenylaminocarbonyl (p-hydroxyphenylaminocarbonyl),
p-methoxyphenylaminocarbonyl, m-chlorophenylaminocarbonyl),
diphenylaminocarbonyl, hydroxyaminocarbonyl,
N-hydroxy-N-methylaminocarbonyl, and
N-hydroxy-N-phenylaminocarbonyl. The cyclic aminocabonyl includes
morpholinocarbonyl and piperidinocarbonyl.
The quinone compounds represented by the general formula (I) and
the hydroquinone derivatives thereof (IIb) may be the salts of
inorganic acids such as hydrochloric acid, nitric acid, and
phosphoric acid, or of organic acids such as methanesulfonic acid,
toluenesulfonic acid, benzenesulfonic acid, and succinic acid.
The compounds represented by the general formula (I) of this
invention are able to be produced by the reaction of a compound
represented by the general formula (II) with an oxidant.
The kind of the oxidant used and the conditions of the oxidation of
a compound represented by the general formula (II) vary according
to the species of R.sup.6 and R.sup.7.
The compounds in which R.sup.6 and R.sup.7 are hydrogen atoms in
the general formula (II), i.e. phenol compounds, are able to be
easily converted into quinone compounds (I) by using a Fremy's salt
as the oxidant. The amount of the Fremy's salt used is 2 to 4 moles
per 1 mole of the compound (II), the solvent being preferably
methanol, acetonitrile, ethanol, dioxane, 1,2-dimethoxyethane, or a
aqueous solvent thereof. The reaction temperature is
10.degree.-80.degree. C. and the reaction time is usually about
2-10 hours.
The compounds in which R.sup.6 is a hydrogen atom and R.sup.7 is a
hydroxyl group in the general formula (II), i.e. hydroquinone
compounds, are able to be easily converted into quinone compounds
(I) by using a mild oxidant such as air, oxygen, a Fremy's salt,
ferric chloride, ferric sulfate, hydrogen peroxide and a peracid.
Such reactions are usually conducted in the presence of a solvent,
and such solvents include methanol, acetonitrile, dioxane,
1,2-dimethoxyehtane and aqueous solvents consisting of the said
organic solvents and water. When air or oxygen is used as the
oxidant, the reaction is carried out at a neutral or weakly
alkaline pH (pH 7.0-pH9.0). A buffer solution (e.g. phosphate
buffer) is used to maintain the pH. The reaction temperature is
-10.degree. C. to 30.degree. C., and the reaction time is usually
within 2 hours. When the oxidant used is ferric chloride, ferric
sulfate or a Fremy's salt, the amount of the oxidant used is
preferably about 1 to 2 moles per 1 mole of the compound (II). The
reaction temperature is -10.degree. C. to 30.degree. C., and the
reaction time is usually within 1 hour.
The compound (II) in which R.sup.6 is methyl, methoxymethyl,
benzyl, or 2-tetrahydropyranyl group, and R.sup.7 is methoxy,
methoxymethyloxy, benzyloxy, or 2-tetrahydropyranyloxy group, i.e.
hydroquinone diether compounds, are able to be easily converted
into quinone compounds (I) by using silver oxide (AgO) or
cerium(IV) ammonium nitrate (hereinafter abbreviated as CAN) as the
oxidant. When silver oxide (AgO) is used the reaction is conducted
in water or a aqueous organic solvent (e.g. dioxane, acetonitrile)
in the presence of nitric acid at -10.degree. C. to 30.degree. C.
When CAN is used as the oxidant, the reaction is conducted in a
aqueous organic solvent (e.g. acetonitrile, methanol), especially
aqueous acetonitrile, in the presence of CAN alone or CAN together
with pyridine-2,6-dicarboxylic acid N-oxide,
pyridine-2,4,6-tricarboxylic acid or pyridine-2,6-dicarboxylic acid
or the like. The suitable mixing ratio of CAN and the pyridine
carboxylic acid described above is usually about 1:1 (molar
equivalent). The reaction temperature is about -5.degree. C. to
about 30.degree. C.
The compounds in which R.sup.5 is carbamoyloxymethyl,
hydroxyaminocarbonyl, N-substituted hydroxyaminocarbonyl,
hydroxymethyl, carboxyl, alkoxycarbonyl, aminocarbonyl, or
substituted aminocarbonyl group are derived from the compounds in
which R.sup.5 is hydroxymethyl, carboxyl, alkoxycarbonyl, or
acyloxymethyl group by the per se known reactions described below.
##STR8## (wherein R.sup.1 R.sup.2, R.sup.3, R.sup.4, n, m, k, and Z
are the same as described above); R.sup.9 and R.sup.10 are
C.sub.1-3 alkyl groups (e.g. methyl, ethyl, propyl); and R.sup.11
and R.sup.12 are hydrogen atoms, C.sub.1-7 lower alkyl groups (e.g.
methyl, ethyl, propyl, i-propyl, butyl, pentyl, hexyl) or aryl
groups (e.g. phenyl, naphthyl)].
The hydroquinone compounds represented by the general formula (IIb)
are able to be produced by protective group removing reaction (acid
hydrolysis) of a compound represented by the general formula (IIa).
When R.sup.8 is a methyl group in the general formula (IIa), the
acid catalyst is preferably hydrogen bromide and the solvent is
preferably acetic acid or water. The reaction temperature is
60.degree. C.-120.degree. C., preferably about 80.degree. C. When
R.sup.8 is a methoxymethyl group or 2-tetrahydropyranyloxy group in
the general formula (IIa), the acid catalyst used is an organic or
inorganic acid such as sulfuric acid, methanesulfonic acid,
p-toluenesulfonic acid, and camphorsulfonic acid, and the solvent
is methanol, ethanol, or an aqueous organic solvent (e.g. methanol,
acetone, tetrahydrofuran, ether, acetonitrile). The reaction
temperature is 20.degree.-80.degree. C., preferably
50.degree.-60.degree. C.
When R.sup.8 is a benzyl group, the compounds (IIb) are able to be
produced by catalytic reduction by a usual method of a compound
(IIa) in the presence of a catalyst such as palladium-carbon.
The compounds in which, in the general formula (I), n is 0, Z is
--CH.dbd.CH--, k is an integer from 0 through 7, and m is 1, or the
compounds in which n is an integer from 4 through 11 and m is 0,
that is, the compounds represented by the following formula
##STR9## [wherein, R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.5
are the same as described above, A refers to the formula
--(CH.sub.2).sub.k'+4 (wherein k' is an integer from 0 through 5)
or A-R.sup.5 refers to the formula --CH.dbd.CH--(CH.sub.2).sub.k'+2
-R.sup.5 (wherein k' and R.sup.5 are the same as described above)]
are able to be produced by sulfur eliminating reduction of a
compound represented by the general formula ##STR10## (wherein, the
symbols are the same as described above), followed by oxidation of
the products.
The sulfur eliminating reduction of a compound represented by the
general formula (Ib) is conducted by using Raney nickel. The
reaction is conducted in a solvent such as methanol, ethanol and
ethyl acetate, in the presence of about 10 to 20 times by weight of
Raney nickel when hydrogen gas is not used, and at a temperature in
the range from the room temperature to 100.degree. C. Five to 10
times by weight of Raney nickel is used when hydrogen gas is
present and a pressure of 5-200 atm is applied. The compounds
produced by the sulfur eliminating reduction are hydroquinone
derivatives, and therefore are converted into quinone compounds
(Ia) by oxidation with ferric chloride or air as required.
The quinone compounds (I) and the hydroquinone derivatives thereof
(IIb) thus produced are able to be isolated by the per se known
methods for isolation and purification (e.g. chromatography,
crystallization).
The quinone compounds (I) and the hydroquinone derivatives thereof
(IIb) of this invention can be converted from one to the other by
chemical or biochemical oxidation or reduction of the quinone
nucleus or the hydroquinone nucleus of the compounds. In general,
hydroquinone derivatives (IIb) are susceptible to oxidation with
oxygen, air or the like, and therefore usually treated as the
corresponding stable quinone compounds (I). Because hydroquinone
compounds (IIb) and quinone compounds (I) are easily converted from
one to the other by chemical or biochemical oxidation-reduction,
the quinone compounds (I) and the hydroquinone derivatives (IIb)
are considered to have equivalent properties when the compounds
exert their pharmaceutical actions under physiological
conditions.
The quinone compounds (I) are able to be easily converted into the
hydroquinone compounds (IIb) by a per se known method using a mild
reductant such as sodium hydrosulfite, sodium hydrogen sulfite and
sodium borohydride, or by catalytic reduction in the presence of
platinum oxide, or palladium-carbon.
Some quinone compounds (I) and (IIb) have structurally an
asymmetric center at the alpha (.alpha.) carbon on the side chain
of the quinone or hydroquinone nucleus, and such compounds are
optically active. This implies that the compounds (I) and (IIb) of
this invention include optically active compounds as well as
racemic compounds.
Each of the compound (I) and (IIb) of this invention exert
improvement effect of metabolism of polycarboxylic unsaturated
fatty acids (linoleic acid, .gamma.-linolenic acid,
.alpha.-linolenic acid, arachidonic acid, dihomo-.gamma.-linolenic
acid, eicosapentaenoic acid), among the effect particularly two or
more of inhibition of production of fatty acid peroxide
(antioxidation), inhibition of production of metabolites by
5-lipoxygenase system (e.g. leucotrienes, 5-hydroxyeicosatetraenoic
acid, 5-peroxyeicosatetraenoic acid, lipoxines), inhibition of
thromboxane A.sub.2 synthetase, thoromboxane A.sub.2 receptor
antagonism, and scavenging action of active oxygen species, and
have very little toxicity and very few side effects. Therefore the
compounds (I) and (IIb) are expected to be useful for treatment and
prevention of diseases in mammals (mouse, rat, rabbit, dog, monkey,
human, etc.), such as thrombosis, ischemic diseases (e.g.
myocardial infarction, cerebral stroke) due to contraction or
twitch of arterial smooth muscle in heart, lung, brain and kidney,
nephritis, pulmonary failure, bronchial asthma, psoriasis,
inflammation, immediate allergy, arteriosclerosis, atherosclerosis,
fatty liver, hepatitis, cirrhosis of the liver, hypersensitivity
pneumonitis, immunodeficiency, diseases of cardiovascular system
(myocardial infarction, cerebral stroke, nephritis, etc.) due to
disorder of tissues, enzymes, and cells caused by active oxygen
species (superoxides, hydroxide radicals, lipid peroxides, etc.),
and cancer, being useful as medicines such as antithrombotics,
anti-vascular constriction agents, anti-asthma agent, antiallergic
agents, therapeutics for psoriasis, agents for improvement of
heart, brain and cardiovascular system, therapeutics for nephritis,
active oxygen-eliminating agents, anticancer agents, agents for
improvement of control of arachidonate cascade products, etc.
Because the compounds of this invention have low toxicity, the
compounds as they are or as pharmaceutical compositions produced by
mixing with a per se known, pharmaceutically acceptable carrier or
excipient or the like [e.g. tablets, capsules (including soft
capsules and microcapsules), liquid preparations, injections,
suppositories] are able to be given safely orally or parenterally.
The dose varies according to the subjects to be treated, the route
of administration, symptoms, etc. For example, when given orally to
an adult patient with thrombosis, the unit dose is usually about
0.1 mg/kg-20 mg/kg body weight, preferably about 0.2 mg/kg-10 mg/kg
body weight which is desirably given about 1-3 times a day.
The compounds (II) are able to be produced by one of the following
methods.
The compounds represented by the general formula (IIb) described
above are able to be produced by condensation of a hydroquinone
compound represented by the general formula ##STR11## (wherein,
R.sup.1 is the same as described above) with a compound represented
by the general formula ##STR12## (wherein, k, m, n, R.sup.5 and Z
are the same as described above, and X is hydroxyl or acetoxy
group) in the presence of an acidic catalyst. The said acidic
condensation is carried out without solvent or in an organic
solvent, in the presence of concentrated sulfuric acid,
trifluoromethylsulfonic acid, or fluorosulfonic acid in the
atmosphere of nitrogen or argon gas. The reaction solvents include
methylene chloride, 1,2-dichloroethane, benzene, and toluene. The
reaction temperature is 30.degree.-100.degree. C., preferably
60.degree.-90.degree. C. The amount of the catalyst is 1.2-5 mole
equivalents, preferably 2-3 times moles.
Among the compounds represented by the general formula (II), the
compounds in which R.sup.6 is methyl and R.sup.7 is methoxy group
are able to be synthesized, for example, by the procedure described
below. ##STR13## (wherein, R.sup.1, R.sup.2, R.sup.3 and n are the
same as described above; R.sup.13 is a hydrogen atom, methyl group
or hydroxyl group which may be substituted; R.sup.14 is a hydrogen
atom, methyl group, hydroxyl group which may be substituted, or
carboxyl group which may be substituted).
That is, an intermediate (VI) is able to be produced by the
reaction of a pyridylketone derivative (V) with a compound
represented by the general formula ##STR14## (wherein, R.sup.1,
R.sup.2, and R.sup.3 are the same as described above, and Y is Li
or MgBr). This condensation can be carried out in anhydrous diethyl
ether or anhydrous tetrahydrofuran, in the atmosphere of nitrogen
or argon at -80.degree.-20.degree. C. Dehydration proceeds when the
said intermediate (VI) is allowed to react in the presence of an
acid catalyst (e.g. concentrated sulfuric acid, p-toluenesulfonic
acid) in an organic solvent (e.g. acetic acid, methylene chloride,
1,2-dichloroethane) at 10.degree.-100.degree. C. for 1-3 hours, to
give an olefin compound (VII). The said olefin compound (VII) is
subjected to catalytic reduction in an organic solvent (e.g. acetic
acid, ethanol, ethyl acetate) in the presence of a catalyst (e.g.
palladium-carbon, palladium black), to give a compound (VIII). The
compound (VIII) is able to be converted into a carboxylic acid
derivative (IIc) by a routine method.
Among the compounds represented by the general formula (II), the
compounds represented by the following formulas (IId and IIe) are
able to be produced also by the following procedure. ##STR15##
(wherein, R.sup.1 and R.sup.2 are the same as described above).
That is, reaction of the bromide derivative (X) with 2-, 3-, or
4-pyridyl lithium in an anhydrous solvent (e.g. tetrahydrofuran,
diethyl ether) in the atmosphere of an inert gas (e.g. nitrogen
gas, argon, helium), to give a compound (IId). The imidazolyl
derivative (IIe) is able to be produced by the reaction of the
bromide derivative (X) with imidazole in the presence of an
acid-binding agent (e.g. triethylamine, sodium hydride) in
dimethylformamide or dimethylsulfoxide.
The novel quinone derivatives of this invention are effective in
improvement of metabolism of poly-unsaturated fatty acids,
particularly control of biosynthesis of arachidonate cascade
products (inhibition of 5-lipoxygenase, inhibition of TXA.sub.2
synthetase, TXA.sub.2 receptor antagonism) and active oxygen
species elimination, and useful as medicines for improvement of
dysfunction and circulatory systems in heart, brain, lung and
kidney, as antiasthma agents, as antiallergic agents, etc.
EXAMPLE 1
Compound No. 1
To a solution of 4.0 g (32.5 mmol) of 1- (3-pyridyl)ethanol in 25
ml of dichloroethane, 4.96 g (32.6 mmol) of
2,3,5-trimethylhydroquinone and 4.5 ml (50.9 mmol) of
trifluoromethanesulfonic acid were added and refluxed by heating
for 20 hours in argon atomosphere. After cooling, ice water was
added, washed with ethyl acetate to eliminate neutral substances,
and made weakly alkaline with a saturated solution of sodium
hydrogen carbonate. The resultant substance was extracted with
ethyl acetate, and the extract was washed with water, dried,
oxidized with air and concentrated under reduced pressure. The
residue was purified with silica gel column chromatography
(isopropyl ether-ethyl acetate (1:2)), to give 5.1 g of
3,5,6-trimethyl-2-[1-(3-pyridyl)ethyl]-1,4-benzoquinone (yield
61%). Physical data of this compound are shown in Table 1.
EXAMPLE 2
Compound No. 2
to a solution of 1.0 g (5.4 mmol) of phenyl-(3-pyridyl) methanol
and 823 mg (5.4 mmol) of 2,3,5-trimethylhydroquinone in 15 ml of
dichloroethane, 0.5 ml (9.4 mmol) of concentrated sulfuric acid was
added, and refluxed by heating for 2 hours. The reaction mixture
was made weakly alkaline with a saturated aqueous solution of
sodium hydrogen carbonate, from which the organic phase was
separated while the aqueous phase was extracted with chloroform and
the extract was combined with the organic phase. The organic phase
was washed with water, dried, and oxidized with air, from which the
solvent was evaporated off. The residue was purified with silica
gel column chromatography (isopropyl ether-ethyl acetate (1:1)), to
give 1.25 g (72.7%) of
3,5,6-trimethyl-2-[phenyl-(3-pyridyl)methyl]-1,4-benzoquinone. The
physical data are shown in Table 1.
EXAMPLE 3
Compound No. 3
To a solution of 1.0 g (3.36 mmol) of ethyl
4-[hydroxy-(3-pyridyl)]methyl-.alpha.-methylcinnamate in 10 ml of
dichloroethane, 514 mg (3.38 mmol) of 2,3,5-trimethylhydroquinone
and 0.28 ml (5.26 mmol) of concentrated sulfuric acid were added
and refluxed by heating for 2 hours. The reaction mixture was made
weakly alkaline with a saturated solution of sodium hydrogen
carbonate, and the organic phase was separated while the aqueous
phase was extracted with chloroform and the extract was combined
with the organic phase. The organic phase was oxidized with ferric
chloride, washed with water, dried, and concentrated. The residue
was purified with silica gel column chromatography (isopropyl
ether-acetic ester (1:1)), to give 1.2 g (yield 82.7%) of ethyl
4-[3,5,6-trimethyl-1,4-benzoquinon
-2-yl(3-pyridyl)methyl]-.alpha.-methylcinnamate. The physical data
are shown in Table 1.
EXAMPLE 4
Compound No. 4
4-[3,5,6-trimethyl-1,4-benzoquinon-2-yl-(3-pyridyl)methyl]-.alpha.-methylci
nnamic acid, 0.7 g (1.75 mmol), was hydrogenated with 0.2 g of 5%
Pd-carbon in 6 ml of acetic acid (the reaction completed in about 2
hours). The catalyst was filtered off, and the filtrate was
concentrated, to which water was added and neutralized with a
saturated aqueous solution of sodium hydrogen carbonate. The
resultant substance was extracted with ethyl acetate, and oxidized
by shaking with an aqueous solution of ferric chloride. After the
organic phase was washed with water and dried, the solvent was
evaporated off and the residue was purified with silica gel column
chromatography (ethyl acetate-ethanol (9:1)) and recrystallized
from ethyl acetate, to give 0.3 g (44.2%) of
3-(4-[3,5,6-trimethyl-1,4-benzoquinon-2-yl-(3-pyridyl)methyl]phenyl)propio
nic acid. The physical data are shown in Table 1.
In a similar way, Compound No. 13 and Compound No. 16 were
prepared. The physical data are shown in Table 2-1.
EXAMPLE 5
Compound No. 5
Ethyl
4-[3,5,6-trimethyl-1,4-benzoquinon-2-yl-(3-pyridyl)methyl]-.alpha.-methylc
innamate, 1.2 g (2.8 mmol), was dissolved in 20 ml of concentrated
hydrochloric acid, and refluxed by heating for 2 hours. After
cooling, the reaction mixture was neutralized with a saturated
aqueous solution of sodium hydrogen carbonate, and the resulting
substance was extracted with ethyl acetate. The extract was washed
with water and dried, and the solvent was evaporated off. The
residue was purified with silica gel column chromatography (ethyl
acetate-ethanol(9:1)), and recrystallized from ethyl acetate, to
give 0.96 g (85.6%) of
4-[3,5,6-trimethyl-1,4-benzoquinon-2-yl(3-pyridyl)methyl]-.alpha.-methylci
nnamic acid. The physical data are shown in Table 1.
EXAMPLE 6
Compound No. 6
The solution of 400 mg (1.12 mmol) of
5-(2,5-dimethoxy-3,4,6-trimethylphenyl)-5-(3-pyridyl)pentanoic acid
in 8 ml of acetonitrile-water (1:1) was cooled to 0.degree. C., to
which the solution of 1.55 g (2.82 mmol) of cerium ammonium nitrate
in 6 ml of acetonitrile-water (1:1) was added with stirring. The
reaction mixture was stirred for 30 minutes, neutralized with
sodium hydrogen carbonate, and extracted with ethyl acetate. The
extract was washed with water and dried, and the solvent was
evaporated off. The residue was purified with silica gel column
(ethyl acetate), and recrystallized from ethanol, to give 200 mg
(54.3%) of 5-(3,5,6-trimethyl-1,4-benzoquinon
-2-yl)-5-(3-pyridyl)pentanoic acid.
According to the methods described in the Example, Compounds No. 7
to No. 15, Compounds No. 19 and No. 21 were prepared. The data of
these compounds are shown in Table 2-1 or Table 2-2.
EXAMPLE 7
Compound No. 16
To a solution of 1.1 g (3.09 mmol) of
1-(3,6-dimethoxy-2,4,5-trimethylphenyl)-1-(3-pyridyl)heptane in 20
ml of acetonitrile-water (1:1), the solution of 4.5 g (8.2 mmol) of
cerium ammonium nitrate (CAN) in 15 ml of acetonitrile-water was
added dropwise with stirring at 0.degree. C. and stirred for 30
minutes after the completion of addition. The reaction product was
isolated by a routine method, to give 635 mg (63%) of
1-(3,5,6-trimethyl-1,4-benzoquinon -2-yl)-1-(3-pyridyl)heptane. The
physical data are shown in Table 2-1.
EXAMPLE 8
Compound No. 17
3,5,6-trimethyl-2-[1-(3-pyridyl)ethyl]-1,4-benzoquinone
hydrochloride
To a solution of 5.4 g (21.2 mmol) of
3,5,6-trimethyl-2-[1-(3-pyridyl)ethyl]-1,4-benzoquinone in ethanol
(30 ml), 1.8 ml of concentrated hydrochloric acid was added and the
resultant solution was concentrated under reduced pressure. To the
residue ethyl acetate was added and the resultant crystals were
collected by filtration and recrystallized from ethanol-ethyl
acetate, to give 5.6 g (91%) of
3,5,6-trimethyl-2-[1-(3-pyridyl)ethyl]-1,4-benzoquinone
hydrochloride.
According to the method described in the Example, Compound No. 18
and Compound No. 24 were prepared from Compound No. 14 and Compound
No. 23, respectively.
Physical data are shown in Table 2-1.
EXAMPLE 9
Compound No. 13
7-(3-pyridyl)-7-(3,5,6-trimethyl-1,4-benzoquinon -2-yl)-6-heptenoic
acid (2.5 g) was hydrogenated in the presence of 5%
palladium-carbon (0.5 g) in acetic acid (20 ml) (the reaction
completed in about 2 hours). The catalyst was removed, the solvent
was concentrated, and water (10 ml) and methanol (40 ml) were
added. This solution was neutralized by addition of a saturated
solution of sodium hydrogen carbonate, and the hydroquinone
derivative was oxidized by aeration. After completion of oxidation,
the mixture was concentrated under reduced pressure and the product
was extracted with chloroform. The organic phase was dried with
magnesium sulfate and concentrated under reduced pressure. The
residue was dissolved in ethyl acetate and purified with silica gel
column chromatography [ethyl acetate-ethanol(9:1)] and
recrystallized from a mixture of ethyl acetate-isopropyl ether, to
give 7-(3-pyridyl)-7-(3,5,6-trimethyl-1,4-benzoquinon
-2-yl)heptanoic acid (2.1 g).
According to the method described in the Example 9, Compound No. 16
was synthesized from 1-(3-pyridyl)-1
-(3,5,6-trimethyl-1,4-benzoquinon -2-yl)-1-heptane. Physical
properties and nuclear magnetic resonance spectrum are shown in
Table 2-1.
EXAMPLE 10
Compound No. 22
A solution of 0.6 g (2.3 mmol) of
1-(2,5-dimethoxy-3,4,6-trimethylbenzyl)imidazole in 8 ml of
acetonitrile-water (1:1) was cooled to 0.degree. C., to which a
solution of 3.1 g (5.64 mmol) of cerium ammonium nitrate in 5 ml of
acetonitrile-water (1:1) was added with stirring. The reaction
mixture was stirred for 30 minutes, made weakly alkaline with an
aqueous solution of sodium hydrogen carbonate, and extracted with
ethyl acetate. The extract was washed with water and dried, and the
solvent was evaporated off. The residue was purified with silica
gel column chromatography (ethyl acetate). The eluate from the
column was concentrated, to which ethanol was added and then 0.2 ml
of concentrated hydrochloric acid was added. The solution was
concentrated and the resulting crystals were collected by
filtration, to give 0.3 g (48.9%) of
2-[(1-imidazolyl)methyl]-3,5,6-trimethyl-1,4-benzoquinone
hydrochloride.
Physical properties and nuclear magnetic resonance spectrum of this
compound are shown in Table 2-3.
EXAMPLE 11
compound No. 23
The mixture of 3.6 g (17.9 mmol) of
(3-pyridyl)-(2-thienyl)methanol, 2.74 g (18.0 mmol) of
2,3,5-trimethylhydroquinone and 2.3 ml of methanesulfonic acid, and
45 ml of dichloroethane was stirred at 60.degree. C. for 2
hours.
After cooling, an aqueous solution of sodium hydrogen carbonate was
added to the reaction mixtrue, the organic phase was separated and
the water phase was extracted with chloroform. The extract was
added to the organic phase, shake with 50 ml of the aqueous
solution of 5.8 g (21. 5 mmol) of ferric chloride, and made weakly
alkaline with an aqueous solution of sodium hydrogen carbonate,
from which the organic phase was separated. The organic phase was
washed with water, dried, concentrated, and purified with silica
gel column chromatography (ethyl acetate), to give 6.0 g (92.3%) of
2-[(3-pyridyl)(2-thienyl)methyl]-3,5,6-trimethyl-1,4-benzoquinone.
Physical properties and nuclear magnetic resonance spectrum of the
compound described above are shown in Table 2-3.
EXAMPLE 12
Another Method for Production Compound No. 7
The solution of 1.2 g (3.7 mmol) of
2-[(3-pyridyl)(2-thienyl)methyl]-3,5,6-trimethyl-1,4-benzoquinone
in 20 ml of ethanol was refluxed by heating in the presence of 24 g
of Raney nickel (W-6) for 5 hours. After cooling the catalyst was
removed by filtration, and the filtrate was concentrated and
redissolved in ethyl acetate and shaken with the solution of 1.2 g
of ferric chloride in 10 ml of water. The mixture was made weakly
alkaline with sodium hydrogen carbonate, from which the organic
layer was separated, washed with water, dried, and concentrated.
The residue was purified with silica gel column chromatography
(ethyl acetate-isopropyl ether (1:1)), to give 0.8 g (72.5%) of
2-[1-(3-pyridyl)pentyl]-3,5,6-trimethyl-1,4-benzoquinone (Compound
No. 7).
EXAMPLE 13
7-(2,5-dimethoxy-3,4,6-trimethylphenyl)-7-(3-pyridyl)heptanoic acid
(1.0 g, 2.6 mmol) prepared in the Reference Example 11 was
dissolved in 47% aqueous hydrogen bromide (5 ml) and the solution
was heated at a reflux temperature for 2 hours. After the reaction
was completed, the reaction mixture was cooled. The solution was
made alkaline with sodium bicarbonate and the product was extracted
with ethylacetate. The extract was washed with water, dried, and
evaporated in vacuo. The resulting hydroquinone was oxidized with
air and the solvent was evaporated to yield
7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-7-(3-pyridyl)heptanoic
acid (0.8 g, 86.8%) after crystallization from ethylacetate, m.p.
126.degree.-127.degree. C.
8-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-8-(3-pyridyl)octanoic
acid, m.p. 113.degree.-114.degree. C. was prepared from
8-(2,5-dimethoxy-3,4,6-trimethylphenyl)-8-(3-pyridyl)octanoic acid
by a similar procedure of the above example.
TABLE 1 ______________________________________ Pre- pared Molecular
by the formula pro- physical Com- cedure proper- Nuclear magnetic
resonance pound of Ex- ties spectrum, .delta. value (ppm) in No.
ample m.p. CDCl.sub.3, TMS as internal standard
______________________________________ 1 1 C.sub.16 H.sub.17
NO.sub.2 1.63(3H, d, J=3.0Hz), 1.97(3H, s), oil 2.00(6H, s),
4.50(1H, quartet, J= 6Hz), 7.27(1H, dd, J=7.5 & 4.5Hz),
7.67(1H, dt, J=7.5 & 1.5Hz), 8.45 (1H, dd, J=4.5 & 1.5Hz),
8.47(1H, d, J=1.5Hz) 2 2 C.sub.21 H.sub.19 NO.sub.2 1.90(3H, s),
1.97(3H, s), 2.02(3H, oil s), 5.90(1H, s), 7.05-7.35(6H, m),
7.50(1H, dt, J=4.5 & 1.5Hz), 8.45 (2H, m) 3 3 C.sub.27 H.sub.27
NO.sub.4 1.30(3H, t, J=7.0Hz), 1.92(6H, s), oil 1.97(3H, s),
2.03(3H, s), 2.10(3H, d, J=1.5Hz), 4.25(2H, q, J=7.0Hz), 5.90(1H,
s), 7.17(2H, ABd, J=7.5 Hz), 7.37(2H, ABd, J=7.5Hz), 7.50 (1H, dt,
J=7.5 & 1.5Hz), 7.67(1H, m), 8.47(1H, d, J=1.5Hz), 8.50(1H, dd,
J=4.5 & 1.5Hz) 4 4 C.sub.24 H.sub.23 NO.sub.4 in
dimethylsulfoxide-d.sub.6 : 205-207.degree. C. 1.33(3H, s),
1.90(3H, s), 1.93(3H, d, J=1.0Hz), 2.50(2H, m), 2.70(2H, m),
5.80(1H, s), 7.03(2H, d, J=7.5 Hz), 7.18, 2H, d, J=7.5Hz), 7.27
(1H, dd, J=7.5 & 4.5Hz), 7.50(1H, dt, J=7.5 & 1.5Hz),
8.37(2H, m) 5 5 C.sub.25 H.sub.23 NO.sub.4 2.03(6H, s), 2.13(3H, d,
J=1.0Hz), 199-201.degree. C. 5.90(1H, s), 7.17(2H, d, J=7.5Hz),
7.30(1H, dd, J=7.5 & 4.5Hz), 7.40 (2H, d, J=7.5Hz), 7.60(1H,
dt, J= 7.5 & 1.5Hz), 7.77(1H, s), 8.47(1H, d, J=1.5Hz),
8.57(1H, dd, J=4.5 & 1.5Hz), 10.40(1H, broad s) 6 6 C.sub.19
H.sub.21 NO.sub.4 1.60(2H, m), 1.93(3H, s), 1.97(3H, 82-84.degree.
C. s), 2.10(2H, s), 2.25(2H, m), 2.33 (2H, t, J=6.8Hz), 4.30(1H, t,
J= 7.5Hz), 7.27(1H, dd, J=7.5 & 4.5 Hz), 7.75(1H, dt, J=7.5
& 1.5Hz), 7.80(1H, broad s), 8.43(1H, dd, J= 4.5 & 1.5Hz),
8.53(1H, d, J=1.5Hz) ______________________________________
TABLE 2-1
__________________________________________________________________________
##STR16## Molecular Prepared by formula Com- the proce- physical
Nuclear magnetic resonance spectrum, pound dure of properties
.delta. value (ppm) in CDCl.sub.3, TMS as internal No. n R.sup.5
Example m.p. standard
__________________________________________________________________________
7 4 H 6, 12 C.sub.19 H.sub.23 NO.sub.2 0.87(3H, t, J=6Hz), 1.30(4H,
m), 1.93(3H, s), 2.00(3H, oil s), 2.10(3H, s), 2.20(2H, m),
4.23(1H, t, J=7.5Hz), 7.20(1H, dd, J=7.5&4.5Hz), 7.70(1H, dt,
J=7.5&1.5Hz), 8.40(1H, dd, J=4.5&1.5Hz), 8.47(1H, d,
J=1.5Hz) 8 3 CH.sub.2 OH 6 C.sub.19 H.sub.23 NO.sub.3 1.10-1.80(4H,
m), 1.93(3H, s), 1.97(3H, s), 2.08(3H, s), 104-105.degree. C.
2.00-2.40(2H, m), 3.60(2H, t, J=6.0Hz), 4.23(1H, t, J=7.5Hz),
7.23(1H, dd, J=7.5&4.5Hz), 7.70(1H, dt, J=7.5&1.5Hz),
8.37(1H, dd, J=4.5&1.5Hz), 8.47(1H, d, J=1.5Hz) 9 3 ##STR17## 6
C.sub.21 H.sub.25 NO.sub.4 oil 1.20-1.80(4H, m), 1.97(3H, s),
2.00(3H, s), 2.03(3H, s), 2.13(3H, s), 2.00-2.40(2H, m), 4.06(2H,
t, J=6.8Hz), 4.27(1H, t, J=7.5Hz), 7.27(1H, dd, J=7.5&4.5Hz),
7.75(1H, dt, J=7.5&1.5Hz), 8.47(1H, dd, J=4.5& 1.5Hz),
8.53(1H, d, J=1.5Hz) 10 4 COOH 6 C.sub.20 H.sub.23 NO.sub.4
1.10-1.80(4H, m), 1.97(3H, s), 2.00(3H, s), 2.13(3H, s),
68-69.degree. C. 1.90-2.40(2H, m), 2.33(2H, t, J=6.8Hz), 4.23(1H,
t, J=7.5Hz), 7.27(1H, dd, J=7.5&4.5Hz), 7.77(1H, dt,
J=7.5&1.5Hz), 8.50(1H, dd, J=4.5&1.5Hz), 8.53(1H, d,
J=1.5Hz), 8.80(1H, broad s) 11 4 CH.sub.2 OH 6 C.sub.20 H.sub.25
NO.sub.3 1.20-1.70(6H, m), 1.97(3H, s), 2.00(3H, s), 2.13(3H, s),
oil 2.00-2.40(2H, m), 3.60(2H, t, J=6.0Hz), 4.27(1H, t, J=7.5Hz),
7.25(1H, dd, J=7.5&4.5Hz), 7.75(1H, dt, J=7.5&1.5Hz),
8.47(1H, dd, J=4.5Hz&1.5Hz), 8.53(1H, d, J=1.5Hz) 12 4
##STR18## 6 C.sub.22 H.sub.27 NO.sub.4 60-61.degree. C. 1.10-
1.80(6H, m), 1.97(3H, s), 2.00(3H, s), 2.03(3H, s), 2.13(3H, s),
1.80-2.30(2H, m), 4.03(2H, t, J=6.0Hz), 4.23(2H, t, J=7.5Hz),
7.23(1H, dd, J=7.5&4.5Hz), 7.73(H, dt, J=7.5&1.5Hz),
8.47(1H, dd, J=4.5& 1.5Hz), 8.53(1H, d, J=1.5Hz) 13 5 COOH 6,
9, 12 C.sub.21 H.sub.25 NO.sub.4 1.10-1.80(6H, m), 1.93(3H, s),
1.98(3H, s), 2.13(3H, s), 126-127.degree. C. 1.90-2.40(2H, m),
2.30(2H, t, J=6.8Hz), 4.23(1H, t, J= 7.5Hz), 7.27(1H, dd,
J=7.5&4.5Hz), 7.80(1H, dt, J= 7.5&1.5Hz), 8.47(1H, dd,
J=4.5&1.5Hz), 8.53(1H, d, J=1.5Hz), 9.85(1H, br) 14 0 H 6
C.sub.15 H.sub.15 NO.sub.2 2.03(6H, s), 2.10(3H, s), 3.87(2H, s),
7.20(1H, dd, J= 66-67.degree. C. 4.5&7.5Hz), 7.53(1H, dt,
J=7.5&1.5Hz), 8.47(1H, dd, J=4.5&1.5Hz), 8.52(1H, d,
J=1.5Hz) 15 2 H 6 C.sub.17 H.sub.19 NO.sub.2 0.93(3H, t, J=7.5Hz),
1.97(3H, s), 2.00(3H, s), 2.10(6H, 56-57.degree. C. s), 2.27(2H, q,
J=7.5Hz), 4.17(1H, t, J=7.5Hz), 7.23(1H, dd, J=7.5&4.5Hz),
7.70(1H, dt, J=7.5&1.5Hz), 8.40(1H, dd, J=4.5&1.5Hz),
8.47(1H, d, J=1.5Hz) 16 6 H 4, 7, 9 C.sub.21 H.sub.27 NO.sub.2
0.87(3H, t, J=6.0Hz), 1.30(10H, m), 1.95(3H, s), 44-45.degree. C.
2.00(3H, s), 2.10(3H, s), 4.23(1H, t, J=7.5Hz), 7.18(1H, dd,
J=7.5&4.5Hz), 7.70(1H, dt, J=7.5&1.5Hz), 8.40(1H, dd,
J=4.5&1.5Hz), 8.48(1H, d, J=1.5Hz) 17 1 H 8 C.sub.16 H.sub.18
NO.sub.2 Cl 1.73(3H, d, J=7.5Hz), 1.90(3H, s), 2.03(3H, s),
2.20(3H, hydro- 188-191.degree. C. s), 4.48(1H, q, J=7.5Hz),
7.93(1H, dd, J=7.5& chloride 4.5Hz), 8.40(1H, d, J=4.5Hz),
8.67(1H, s), 8.70(1H, d, J=4.5Hz) 18 0 H 8 C.sub.15 H.sub.16
NO.sub.2 Cl 2.00(3H, s), 2.03(3H, s), 4.10(2H, s), 7.92(1H, dd, J=
hydro- 164-167.degree. C. 7.5&4.5Hz), 8.36(1H, d, J=4.5Hz),
8.70(1H, s), 8.75(1H, chloride d, J=4.5Hz)
__________________________________________________________________________
TABLE 2-2
__________________________________________________________________________
Prepared Molecular by the formula Com- proce- physical Nuclear
magnetic resonance pound dure of properties spectrum, .delta. value
(ppm) in CDCl.sub.3, No. Formula Example m.p. TMS as internal
standard
__________________________________________________________________________
19 ##STR19## 6 C.sub.17 H.sub.13 NO.sub.2 102-103.degree. C.
2.27(3H, s), 4.00(2H, s), 7.17(1H, dd, J=7.5&4.5Hz), 7.57(1H,
dt, J=7.5&1.5Hz), 7.68(2H, m), 8.07(2H, m), 8.43(1H, dd,
J=4.5&1.5Hz), 8.53(1H, d, J=1.5Hz) 20 ##STR20## 1 C.sub.24
H.sub.21 NO.sub.4 232-233.degree. C. (DMSO-d.sub.6) 1.88(6H, s),
1.95(3H, d, J=1.0Hz), 6.87(1H, s), 6.47(1H, d, J=16.0Hz), 7.15(2H,
d, J=7.5Hz), 7.30(1H, dd, J=7.5&4.5Hz), 7.52(2H, d, J=7.5Hz),
7.53(1H, dt, J=7.5&1.5Hz), 7.57(1H, d, J=16.0Hz), .40(1H, d,
J=1.5Hz), 8.43(1H, dd, J=4.5&1.5Hz), 12.30(1H,) 21 ##STR21## 1
C.sub.16 H.sub.17 NO.sub.2 122-123.degree. C. 1.60(3H, d,
J=3.80Hz), 1.98(6H, s), 2.03(3H, s), 4.50(1H, q, J=3.80Hz),
7.18(2H, A.sub.2 B.sub.2), 8.53(2H, A.sub.2 B.sub.2)
__________________________________________________________________________
TABLE 2-3
__________________________________________________________________________
Prepared Molecular by the formula Com- proce- physical Nuclear
magnetic resonance pound dure of properties spectrum, .delta. value
(ppm) in CDCl.sub.3, No. Formula Example m.p. TMS as internal
standard
__________________________________________________________________________
22 ##STR22## 10 C.sub.13 H.sub.15 N.sub.2 ClO.sub.2 225-228.de
gree. C. 2.03(6H, s), 2.37(3H, s), 5.53(1H, s), 7.27(1H, t, J=
1.5Hz), 7.37(1H, t, J=1.5Hz), 9.80(1H, t, J=1.5Hz) 23 ##STR23## 11
C.sub.19 H.sub.17 NO.sub.2 S oil 2.00(6H, s), 2.03(3H, s), 6.08(1H,
s), 6.83(1H, dd, J= 4.5&1.5Hz), 6.95(1H, dd, J=5.5&4.5Hz),
7.20(1H, dd, J=7.5&4.5Hz), 7.25(1H, dd, J=5.5&1.5Hz),
7.57(1H, dt, J=7.5&1.5Hz), 8.47(2H, m) 24 ##STR24## 8 C.sub.19
H.sub.18 NClO.sub.2 S 185-188.degree. C. decomp. 1.95(3H, s),
2.05(3H, s), 2.22(3H, s), 6.00(1H, s), 7.03(2H, m), 7.37(1H, dd,
J=4.5&1.5Hz), 7.83(1H, dd, J=7.5&4.5Hz), 8.27(1H, broad d,
J=7.5Hz), 8.57(1H, broad s), 8.67(1H, broad d, J=4.5Hz) 25
##STR25## 6, 8 C.sub.15 H.sub.16 HClO.sub.4 152-153.degree. C.
2.18(3H, broad s), 3.98(3H, s), 4.02(3H, s), 4.07(2H, broad s),
7.93(1H, dd, J=7.5&4.5Hz), 8.40(1H, broad d, J=7.5Hz), 8.77(2H,
__________________________________________________________________________
m)
EXAMPLE 14
Example of Pharmaceutical Composition
A) Capsules
______________________________________ (1) Compound No. 1 50 mg (2)
Very fine powder of cellulose 30 mg (3) Lactose 37 mg (4) Magnesium
stearate 3 mg total 120 mg
______________________________________
(1), (2), (3) and (4) were mixed and filled in gelatin
capsules.
B) Soft capsules
______________________________________ (1) Compound No. 17 50 mg
(2) Corn oil 100 mg total 150 mg
______________________________________
According to a routine method, (1) and (2) were mixed and filled in
soft capsules.
C) Tablets
______________________________________ (1) Compound No. 18 50 mg
(2) Lactose 34 mg (3) Corn starch 10.6 mg (4) Corn starch (paste) 5
mg (5) Magnesium stearate 0.4 mg (6) Calcium carboxymethylcellulose
20 mg total 120 mg ______________________________________
According to a routine method, these were mixed and compressed by
tablet machine.
EXPERIMENT 1
Inhibition of 5-lipoxygenase
10.sup.7 RBL-1 cells (rat basophilic leukemia cells) were suspended
in 0.5 ml of MCM (mast cell medium). To the suspension was
subsequently added a solution consisting of 0.5 ml of MCM, 50 .mu.g
of arachidonic acid, 10 .mu.g of A-23187 (calcium ionophore, Eli
Lilly), and a solution of a quinone compound in ethanol at the
final concentration of 1 .mu.M, 0.1 .mu.M, 0.01 .mu.M or 0.001
.mu.M of the test compound was added and allowed to react at
37.degree. C. for 20 minutes. After the reaction, 4 ml of ethanol
containing 1,4-dimethoxy-2-methyl-3-(3-methoxypropyl)naphthalene as
an internal standard were added, mixed well by shaking, and kept at
room temperature for 10 minutes. Then the mixture was centrifuged
for 10 minutes (2000 rpm), and the supernatant was separated. The
supernatant was concentrated to dryness under reduced pressure. To
the concentrate, 0.5 ml of 60 % aqueous methanol was added. One
hundred .mu.l of this solution was subjected to high performance
liquid chromatography for quantitative analysis of 5-HETE
(5-hydroxyeicosatetraenoic acid). The amount of 5-HETE was analyzed
by measurement of the absorbance at 273 nm with a UV absorption
monitor.
Inhibitory effect (IE) of production of 5-HETE is expressed by
(1-b/a).times.100, wherein a is the peak hight or the area
corrected with the peak due to the internal standard in the absence
of the quinone compound, and b is the peak hight or peak area
corrected with the peak due to the internal standard in the
presence of the quinone compound.
The results proved to be the potent inhibition of production of
5-HETE, as shown in Table 5.
EXPERIMENT 2
Inhibition of Thromboxane A.sub.2 (TXA.sub.2) Synthetase
As a preparation of TXA.sub.2 synthetase, horse platelet microsome
treated with indomethacin (indomethacin-treated horse platelet
microsome: IPM) according to the method of Needleman et al.
(Science 193 163, 1979) was used. To 60 .mu.l of the solution of
IPM in 50 mM Tris buffer(pH 7.5) (containing 140 .mu.g on the
protein basis), 60 .mu.l of a solution containing a drug at a
variable concentration was added and kept still at room temperature
for 5 minutes. One hundred .mu.l of this mixture was taken, to
which 20 .mu.l of a buffer containing 30 ng of prostaglandin
H.sub.2 (PGH.sub.2) with ice-cooling and kept still at 0.degree. C.
for 5 minutes to produce thromboxane A.sub.2 (TXA.sub.2). The
reaction was stopped by addition of 500 .mu.l of Tris buffer, and
50 .mu.l of the resultant solution was subjected to
radioimmunoassay of thromboxane B.sub.2 (TXG.sub.2), a stable
metabolite of TXA.sub.2 [Shibouta et al. Biochem. Pharmacol. 28
3601, 1979]. The rate of inhibition (%) of TXA.sub.2 synthetase was
determined from the difference in TXB.sub.2 productivity between
the untreated group and the treated group.
In the following the results of the experiment with some
representative compounds are shown in Table 3.
EXPERIMENT 3
Inhibition of Production of Lipid Peroxide in Rat Brain
Homogenate
Procedure: Sprague-Dawley rats (male, 9-15 weeks old) anesthetized
with pentobarbital (50 mg/kg, intraperitoneal administration) were
venesected and the brain tissue was resected. The tissue was
homogenized in phosphate buffer (pH 7.4), and used as a 5%
homogenate (on weight basis). The brain homogenate was allowed to
react at 37.degree. C. for 1 hour, and the amount of lipid peroxide
produced was determined with the thiobarbituric acid method
according to the method of Okawa et al.(Analytical Biochem 95 551,
1979). The drug was added to the 5% homogenate before the reaction
at 37.degree. C. for 1 hour so that the final concentration might
be 5.times.10.sup.-7 or 10.sup.-6 M. Inhibition of production of
lipid peroxide was expressed as the rate of inhibition in % of the
amount produced in the solvent(DMSO)-treated group.
The results are shown in Table 3.
TABLE 3 ______________________________________ Inhibition of
Inhibition of pro- Inhibition of Thromboxane duction of lipid
production of A.sub.2 (TXA.sub.2) peroxide in rat 5-HETE synthetase
brain homogenate Com- (%) (%) (%) pound Concentration of compound
No. 10.sup.-7M 10.sup.-6M 10.sup.-7M 10.sup.-6M 5 .times.
10.sup.-7M 10.sup.-6M ______________________________________ 1 46
84 37 76 6 90 2 60 85 45 89 32 100 5 28 73 7 65 29 100 7 35 86 --
32 26 100 8 63 88 6 37 20 100 9 62 90 18 54 17 100 10 52 90 24 67
13 100 11 61 88 13 67 15 100 12 67 91 22 56 15 100 13 16 64 48 87
20 84 14 80 92 35 61 46 100 15 57 91 15 76 52 100 16 77 96 6 49 44
100 ______________________________________
EXPERIMENT 4
Effect on Occurrence of Ventricular Arrhythmia Due to
Ischemia-reperfusion in Rat
Procedure: The experiment was carried out in Sprague-Dawley rat
(male, 11-12 weeks old) according to the method of A. S. Manning
(Cir.Res. 55, 545, 1984). A rat was given orally a drug or water at
the dose of 5 ml/kg, and anesthetized 1 hour later with
pentobarbital (50 mg/kg, intraperitoneal injection). The rat was
thoractomized under artificial respiration and the coronary left
anterior descending artery was ligated for 5 minutes, followed by
reperfusion for 10 minutes. The incidences of ventricular
tachycardia, ventricular fibrillation and cardiac arrest observed
for the 10 minutes of reperfusion were determined.
The results are shown in Table 4. Compound No. 1, when given orally
at the dose of 30 mg/kg, inhibited significantly the incidences of
ventricular tachycardia, ventricular fibrillation and cardiac
arrest.
TABLE 4 ______________________________________ Effect on the
occurrence of ventricular arrhythmia due to ischemia-reperfusion in
rat Dose Ventricular Ventricular Cardiac Group mg/kg, p.o.
tachycardia fibrillation arrest
______________________________________ Control -- 18/18 17/18 11/18
group Compound 30 6/8* 3/8** 1/8* No. 1
______________________________________ :The denominator is the
number of rats used and the numerator is the number of rats showing
abnormal cardiac function. :Significance test: X.sup.2 test, *p
< 0.05, **p < 0.01
EXPERIMENT 5
Effect on Cerebral Ischemic Seijure in Spontaneously Hypertensive
Rat
Procedure: A spontaneously hypertensive rat (male, 20-23 weeks old)
was given orally a compound or water at the dose of 5 ml/kg, and 1
hour later anesthetized with pentobarbital. Bilateral common
carotid arteries were ligated, and the interval from immediately
after the ligation to the occurrence of seijure (cramp, jumping,
etc.) was measured.
The results are shown in Table 5. Compound No. 1 given orally at 30
mg/kg prolonged remarkably the interval to the occurrence of
cerebral ischemic seijure. The said compound exerts protective
effects against cerebral ischemia.
TABLE 5 ______________________________________ Effects on cerebral
ischemic seijure in rat Dose Interval till occurrence Group mg/kg,
p.o. of ischemic siejure (min)
______________________________________ Control group -- 122 .+-. 20
Compound No. 1 30 385** .+-. 33
______________________________________ Each group consisted of 5
cases. Student's ttest: **p < 0.01
EXPERIMENT 6
Proteinuria Improving Effect in Rat with Adriamycin-induced
Nephrosis
Procedure: The experiment was carried out with Sprague-Dawley rat
(male, 5 weeks old) according to the method of T. Bertani et al.
[(Laboratory Invest. 46, 16, (1982)]. Adriamycin was given
intravenously at the dose of 7.5 mg/kg and two weeks later urine
was collected for 24 hours after water was loaded orally at 10
ml/kg. Total urinary protein and albumin excreted in the urine were
determined; rats of which total urinary protein was 20 mg/100 g/24
hours or more were chosen for the experiment. The control group
received water (vehicle) alone at 10 ml/kg/day, and the Compound
No. 18 group received the Compound at the dose of 50 mg/kg/day (10
ml/kg, water) once a day for 2 weeks. After 1 week or 2 weeks of
treatment with the drug, 24 hour-urine was collected to deter mine
total urinary protein and albumin. Two weeks later blood was taken
from the thoracic aorta of the rat under pentobarbital anesthesia
(50 mg/kg, intraperitoneal injection) to determine plasma
cholesterol level.
The results are shown in Table 6. The total urinary protein in the
control group increased after two weeks of treatment as compared
with the pretreatment value, and urinary albumin increased both
after 1 week and after 2 weeks of treatment as compared with the
pretreatment value. In Compound No. 18 group, neither total urinary
protein nor urinary albumin differed from the respective
pretreatment values. Furthermore, the serum cholesterol level after
2 weeks was decreased remarkably by the treatment with Compound No.
18. These results prove that the Compound No. 18 improves
adriamycin-induced nephrosis.
TABLE 6 ______________________________________ Improving effect on
adriamycin-induced nephrosis in rat Before 1 week 2 weeks treatment
after after ______________________________________ control (10
ml/kg/day water, p.o., n = 7 total urinary protein 72 .+-. 28 70
.+-. 17 87 .+-. 24* (mg/100 g/24 hr) urinary albumin 23 .+-. 10 37
.+-. 12* 51 .+-. 17** serum cholesterol -- -- 131 .+-. 39 (mg/dl)
Compound No. 18 (50 mg/kg/day, p.o., n = 3) total urinary protein
76 .+-. 28 55 .+-. 17 59 .+-. 9 (mg/100 g/24 hr) urinary albumin 28
.+-. 14 25 .+-. 10 31 .+-. 7 serum cholesterol -- -- 49 .+-. 4#
(mg/dl) ______________________________________ Paired ttest against
pretreatment value *p < 0.05, **p < 0.01 Student's ttest
against the control value #p < 0.05
EXPERIMENT 7
Improving Effect on Glomerulonephritis in Rat
Procedure: Nephritic rat was prepared according to the method of
Matsunaga et al. [Folia pharmacol. japon. 78, 491, (1981)] using
Sprague-Dawley rat (male, 5 weeks old). That is, the rat was
immunized preliminarily by subcutaneous injection of a mixture of 3
mg of rabbit serum albumin (RSA) and an equal volume of Freund's
complete adjuvant, and from two weeks after the RSA was given
intravenously at the dose of 1 mg/rat three times a week for 8
weeks. Then 24 hour-urine was collected to determine total urinary
protein and urinary albumin. Rats of which total urinary protein
was 20 mg/100 g/24 hr or more were chosen for the experiment. The
control group received water (vehicle) alone at 10 ml/kg/day, and
the Compound No. 18 group received the Compound at the dose of 50
mg/kg/day (10 ml/kg, water) once a day for 2 weeks. After 1 week
and 2 weeks of treatment, 24 hour-urine was collected to determine
total urinary protein and urinary albumin.
The results are shown in Table 7. As compared with the control
group, the Compound No. 18 group showed decreased total urinary
protein and urinary albumin. These results prove that the Compound
No. 18 improves nephritis.
TABLE 7 ______________________________________ Improving effect on
glomerulonephritis in rat Before 1 week 2 weeks treatment after
after ______________________________________ control group (water,
10 ml/kg/day, p.o., n = 3) total urinary protein 65 .+-. 21 60 .+-.
20 74 .+-. 9 (mg/100 g/24 hr) urinary albumin 33 .+-. 15 31 .+-. 15
33 .+-. 7 Compound No. 18 group (50 mg/kg/day, p.o., n = 4) total
urinary protein 75 .+-. 28 37 .+-. 8* 48 .+-. 16* (mg/100 g/24 hr)
urinary albumin 45 .+-. 21 17 .+-. 5* 24 .+-. 12*
______________________________________ Paired ttest against
pretreatment value, *p < 0.05
EXPERIMENT 8
Thromboxane A.sub.2 (TXA.sub.2) Receptor Antagonism
Procedure: A spiral strip of the rabbit aorta (2-3 mm wide, about 3
cm long) was suspended in Krebs-Henseleit solution under the load
of 2 g. The Krebs-Henseleit solution was saturated with a mixed gas
of 95%O.sub.2 -5%CO.sub.2 and warmed at 37.degree. C. Inhibition of
the contraction of the vascular strip caused by a TXA.sub.2 mimic
substance, U-46619* (10.sup.-7 M), by pretreatment with Compound
No. 13 30 minutes before was studied.
The results are shown in Table 8
The Compound No. 13 inhibited the vascular contraction caused by
U-46619 by 14% at 10.sup.-6 M, and by 86% at 10.sup.-5 M, thus
exerting a remarkable TXA.sub.2 receptor antagonism.
TABLE 8 ______________________________________ Thromboxane A.sub.2
receptor antagonism Inhibition of con- traction of rabbit aorta
strip due to U- concentration No. of 46619(10.sup.-7 M) drug (M)
cases (% inhibition) ______________________________________
Compound No. 13 10.sup.-6 6 14 .+-. 4 Compound No. 13 10.sup.-5 6
86 .+-. 8 ______________________________________ mean .+-. standard
error
*U-46619:(5Z,9.alpha.,11.alpha.,13E,15S)-15-hydroxy-9,11-(epoxymethano)pr
sta-5,13-diene-1-acid (manufactured by Upjohn Co., U.S.A.)
EXPERIMENT 9
Toxicological Study in the Rat
Procedure:
Five weeks old, male Wistar rats were used. The rats were given the
Compound 18 orally once a day for 14 days at doses of 100 and 300
mg/kg/10 ml of water as a suspension with 5% gum arabic. Control
rats were given vehicle (10 ml/kg of water) alone. After fasting a
night following the final dose of a 2 week treatment, the rats were
anesthetized with ethyl ether and the blood was collected into a
heparinized syringe from the abdominal aorta and the plasma was
separated for the examination of blood chemistry. Blood parameters
such as total protein, glucose, calcium, urea nitrogen, creatinine,
total cholesterol, total bilirubin, alkaline phosphatase (ALP),
leucine aminopeptidase (LAP), lactate dehydrogenase (LDH), glutamic
oxaloacetic transaminase (GOT), glutamic pyruvic transaminase
(GPT), creatine phosphokinase (CPK), albumin and A/G ratio were
analysed by use of auto-analyzer (Hitachi 716). The organs such as
liver, kidney, heart, lung, spleen, adrenal glands, thymus,
testris, brain and hypophysis were excised and weighed. Some organs
(liver, kidney, heart, lung, spleen) were fixed in 10% neutral
formalin solution for histological examinations. Bone marrow was
fixed as well without weighing. These fixed organs were stained
with Hematoxyline-Eosin for histological examinations.
Results:
The rats that received the Compound 18 (300 mg/kg) tended to have a
lower body weight, but the change was not significant (Table 9).
Both doses (100 and 300 mg/kg) produced no significant changes in
any organ weight (Table 9) and produced no changes in the blood
chemistry (Table 10). In the group of 300 mg/kg of the Compound 18,
one of 5 rats showed a mild splenomegaly and increased
extramedullary hematopoiesis. The other organs showed no changes
(Table 11).
TABLE 9
__________________________________________________________________________
Body and organ weights of rats treated with Compound 18 for 2 weeks
B.V. Liver Kidney Heart Lung Spleen Thymus Adrenals Thyroid
Hypophy. Gonads Brain (g) (g) (g) (g) (g) (g) (mg) (mg) (mg) (mg)
(g) (g)
__________________________________________________________________________
Control Mean 176.1 6.684 1.749 0.774 0.949 0.694 0.478 46.2 13.9
9.0 1.930 1.789 SE 3.8 0.166 0.033 0.017 0.038 0.032 0.024 1.1 0.7
0.2 0.059 0.020 Compound Mean 170.3 6.347 1.579 0.709 0.872 0.673
0.450 47.7 11.4 8.3 1.906 1.747 18 SE 4.2 0.222 0.106 0.023 0.025
0.030 0.032 2.8 1.4 1.0 0.029 0.016 100 mg/kg Compound Mean 162.0
6.264 1.508 0.913 0.929 0.703 0.447 43.0 12.0 8.1 1.873 1.714 18 SE
8.3 0.138 0.069 0.194 0.035 0.061 0.028 1.8 1.0 0.4 0.060 0.040 300
mg/kg
__________________________________________________________________________
TABLE 10
__________________________________________________________________________
Blood chemistry-Group menn values (mean .+-. S.D.) Group 1 2 3
Compound Control Compound 18 Compound 18 Dose (mg/kg/day) -- 100
300
__________________________________________________________________________
Number Total Urea Total Total of protein Glucose Calcium nitrogen
Greatinine cholesterol bilirubin Group animals (g %) (mg %) (mg %)
(mg %) (mg %) (mg %) (mg %)
__________________________________________________________________________
1M 5 5.52 .+-. 0.12 102 .+-. 7 10.02 .+-. 0.28 15.7 .+-. 1.1 0.5
.+-. 0.1 51 .+-. 4 0.32 .+-. 0.04 2M 4 5.51 .+-. 0.11 104 .+-. 11
9.84 .+-. 0.41 15.8 .+-. 0.7 0.5 .+-. 0.0 47 .+-. 7 0.27 .+-. 0.03
3M 5 5.48 .+-. 0.20 97 .+-. 11 9.70 .+-. 0.18 14.5 .+-. 0.6 0.4
.+-. 0.1 41 .+-. 14 0.28 .+-. 0.02
__________________________________________________________________________
Number of AI.P LAP LDH GOT GPT GPK Albumin A/G Group Animals (U/l)
(U/l) (U/l) (U/l) (U/l) (U/l) (g %) ratio
__________________________________________________________________________
1M 5 198 .+-. 31 20 .+-. 1 111 .+-. 27 57 .+-. 6 12 .+-. 2 51 .+-.
10 3.44 .+-. 0.10 1.65 .+-. 0.07 2M 4 194 .+-. 32 20 .+-. 1 86 .+-.
22 57 .+-. 6 13 .+-. 1 44 .+-. 5 3.43 .+-. 0.05 1.65 .+-. 0.05 3M 5
149 .+-. 21 19 .+-. 1 99 .+-. 18 64 .+-. 9 14 .+-. 1 52 .+-. 9 3.47
.+-. 0.13 1.73 .+-. 0.07
__________________________________________________________________________
TABLE 11
__________________________________________________________________________
Histological findings in rat treated with Compound 18 for 2 weeks
Compound Dose of Compound 18 Compound 18 Compound 18 (mg/kg/day)
Control 100 300 Rat number 1 2 3 4 5 6* 7 8 9 10 11 12 13 14 15
__________________________________________________________________________
Spleen Widening of red pulp - - - - - / - - - - - + + - -
Congestion (dilatation of sinus) - - - - - / - - - - - - - - -
Extramedullary hematopoiesis + + + + + / + + + + + + ++ + + Atrophy
of white pulp - - - - - / - - - - - + - - - Liver Parenchymal cell
altration - - - - - / - - - - - - - - - Kidney Dilatation of pelvis
+++ - - ++ - / - - ++ + - + - - - Heart Cardiac cell alteration - -
- - - / - - - - - - - - - Lung Alteration - - - - - / - - - - - - -
- - Bone marrow Proliferation of erythroblast - - - - - / - - - - -
- - - -
__________________________________________________________________________
The scores indicate -: negative, +: mild, ++: moderate, +++: severe
*: The rat (No. 6) died of adminstration error during the
experiment. Male Wistar rats at 5 weeks of aged were used. They
received oral adminstration of Compound 18 for 2 weeks. Control
rats received 5% gum arabic solution at 10 ml per kilogram body
weight.
REFERENCE EXAMPLE 1
A solution of 10.0 g (63.3 mmol) of 3-bromopyridine in 100 ml of
ether was cooled to -78.degree. C., to which 40 ml (64 mmol) of
1.6M n-butyllithium hexane solution was added dropwise with
stirring. After completion of the addition, the mixture was stirred
for further 15 minutes, to which the solution of 5.45 g (63.3 mmol)
of .gamma.-butyrolactone in 15 ml of ether was added dropwise, and
stirred for further 1 hour at -78.degree. C.-room temperature. To
the reaction mixture an aqueous solution of ammonium chloride, and
the resultant substance was extracted with ethyl acetate. The
extract was washed with water and dried, and the solvent was
evaporated off. The residue was purified with silica gel column
chromatography (CHCl.sub.3 -MeOH (9:1)) and recrystallized from
ethyl acetate-isopropyl ether, to give 8.0 g (77%) of
4-(3-pyridyl)-4-oxobutanol. m.p. 36.degree.-37.degree. C.
In a similar way, 5-(3-pyridyl)-5-oxopentanol (71%) and
6-(3-pyridyl)-6-oxohexanol (57%) were prepared from
.delta.-valerolactone and from .epsilon.-caprolactone,
respectively.
REFERENCE EXAMPLE 2
A solution of 12.5 g (69.8 mmol) of the alcohol derivative prepared
in Reference Example 1 and 12.6 ml (90.7 mmol) of triethylamine in
100 ml of dimethylformamide were cooled with ice, to which 9.1 g
(83.3 mmol) of trimethylchlorosilane was slowly added dropwise with
stirring. The mixture was stirred for 30 minutes after completion
of the addition and diluted with water, from which the product was
extracted with ethyl acetate. The extract was washed with water and
dried, and the solvent was evaporated off. The residue was
distilled under reduced pressure, to give 13.4 g (76.4%) of
1-(3-pyridyl)-4-trimethysilyloxybutan-1-one (b.p. (1 mm)
126.degree.-130.degree. C.)
In a similar way, 1-(3-pyridyl)-5-trimethylsilyloxypentan-1-one
(b.p.(1 mm) 134.degree.-138.degree. C.) and
1-(3-pyridyl)-6-trimethylsilyloxyhexan-1one (b.p. (1 mm)
140.degree.-143.degree. C.) were prepared.
REFERENCE EXAMPLE 3
A Grignard reagent was prepared from 7.73 g (29.8 mmol) of
1-bromo-2,5-dimethoxy-3,4,6-trimethoxybenzene, 700 mg (28.8 mmol)
of magnesium, and 50 ml of tetrahydrofuran at 65.degree. C., and
the resultant solution was cooled to 0.degree. C., to which the
solution of 6.0 g (23.9 mmol) of the silyl ether derivative
prepared in Reference Example 2 in 10 ml of tetrahydrofuran was
added dropwise with stirring. The mixture was mixed at room
temperature for 1 hour after completion of the addition, to which
water was added and extracted with ethyl acetate. The extract was
washed with water and dried (MgSO.sub.4), and the solvent was
evaporated off. To the residue ethanol (50 ml) and 2N hydrochloric
acid (10 ml) were added and stirred for 1 hour. The reaction
mixture was concentrated under reduced pressure and neutralized
with sodium hydrogen carbonate, from which the product was
extracted with ethyl acetate. The extract was washed with water and
dried, and the solvent was evaporated off. The residue was
dissolved in 80 ml of acetic acid, to which 15 ml of sulfuric acid
was added and stirred at 80.degree. C. for 30 minutes. After
cooling followed by careful addition of 60 g of sodium hydrogen
carbonate, the mixture was diluted with water, from which the
product was extracted with ethyl acetate. The extract was washed
with an aqueous solution of sodium hydrogen carbonate and then with
water, and dried (MgSO.sub.4), from which the solvent was
evapporated off. The residue was purified with silica gel column
chromatography (CHCl.sub.3 -EtOAc (1:1)), to give 4.09 g (43.8%) of
1-acetoxy-4-(2,5-dimethoxy-3,4,6-trimethylphenyl)-4-(3-pyridyl)-3-butene
(an oil).
In a similar way,
1-acetoxy-5-(2,5-dimethoxy-3,4,6-trimethylphenyl)-5-(3-pyridyl)-4-pentene
and
1-acetoxy-6-(2,5-dimethoxy-3,4,6-trimethylphenyl)-6-(3-pyridyl)-5-hexene
were prepared.
REFERENCE EXAMPLE 4
A solution of 1.0 g (2.7 mmol) of the butene derivative prepared in
Reference Example 3 in 10 ml of acetic acid was subjected to a
catalytic reduction at 80.degree. C. in the presence of 0.4 g of 5%
palladium-carbon catalyst. After completion of the reaction, the
catalyst was removed by filtration, and the filtrate was
concentrated under reduced pressure. The residue was dissolved in
ethyl acetate, washed with an aqueous solution of sodium hydrogen
carbonate and then with water, and dried, from which the solvent
was evaporated off. The residue was purified with silica gel column
(ethyl acetate), to give 750 mg (74.6%) of
1-acetoxy-4-(2,5-dimethoxy-3,4,6-trimethylphenyl)-4-(3-pyridyl)butane
(an oil).
In a similar way
1-acetoxy-6-(2,5-dimethoxy-3,4,6-trimethylphenyl)-6-(3-pyridyl)hexane
and
1-acetoxy-5-(2,5-dimethoxy-3,4,6-trimethylphenyl)-5-(3-pyridyl)pentane
were prepared.
REFERENCE EXAMPLE 5
To a solution of 0.7 g (1.88 mmol) of the butane derivative
prepared in Reference Example 4 in 3 ml of methanol, a solution of
0.3 g (7.50 mmol) of sodium hydroxide in 3 ml of water was added
and stirred at room temperature for 30 minutes, to which water was
added. The product was extracted with ethyl acetate, and the
extract was washed with water, dried, and concentrated. The residue
was purified with a silica gel short column (ethyl acetate), to
give 0.5 g (80.5%) of
4-(2,5-dimethoxy-3,4,6-trimethylphenyl)-4-(3-pyridyl)-1-butanol (an
oil).
In a similar way 5-(2,5-dimethoxy-3,4,6-trimethylphenyl)-5
-(3-pyridyl)-1-pentanol (m.p. 99.degree.-100.degree. C.) and
6-(2,5-dimethoxy-3,4,6-trimethylphenyl)-6-(3-pyridyl)-1-hexanol
(m.p. 90.degree.-91.degree. C.) were prepared.
REFERENCE EXAMPLE 6
A solution of 10.0 g (63.3 mmol) of 3-bromopyridine in 100 ml of
ether was cooled to -78.degree. C., to which 40 ml of 1.6M (64
mmol) n-butyllithium hexane solution was added dropwise. The
mixture was stirred for 15 minutes after completion of the
addition, to which a solution of 7.52 g (67.7 mmol) of heptanitrile
in 15 ml of ether was added dropwise and stirred at -78.degree. C.
to room temperature further for 1 hour. To the reaction mixture an
aqueous solution of ammonium chloride was added, from which the
product was extracted with ethyl acetate. The extract was washed
with water and dried, and the solvent was evaporated off. The
residue was purified with silica gel column chromatography (eluted
with isopropyl ether), to give 3.9 g (36%) of 3-heptanoylpyridine
(an oil).
In a similar way 3-propionylpyridine and 3-pentanoylpyridine were
prepared by the reaction with propionitrile and with valeronitrile,
respectively.
REFERENCE EXAMPLE 7
A Grignard reagent was prepared from 693 mg (28.3 g atom) of
magnesium, 7.6 g (29.3 mmol) of
1-bromo-2,5-dimethoxy-3,4,6-trimethylbenzene and tetrahydrofuran at
65.degree. C. and cooled to 0.degree. C., to which a solution of
3.75 g (21.9 mmol) of 3-heptanoylpyridine in 10 ml of
tetrahydrofuran was added dropwise. After completion of the
addition, the reaction mixture was stirred at room temperature for
1 hour, to which water was added and extracted with ethyl acetate.
The extract was washed with water, dried and concentrated. The
residue was purified with silica gel column chromatography
(isopropyl ether) and recrystallized from hexane, to give 3.2 g
(39%) of
1-(2,5-dimethoxy-3,4,6-trimethylphenyl)-1-(3-pyridyl)heptanol. m.p.
109.degree.-110.degree. C.
In a similar way
1-(2,5-dimethoxy-3,4,6-trimethylphenyl)-1-(3-pyridyl)propanol and
1-(2,5-dimethoxy-3,4,6-trimethylphenyl)-1-(3-pyridyl)pentanol were
prepared.
REFERENCE EXAMPLE 8
To a solution of 2.5 g (6.74 mmol) of the alcohol derivative
prepared in Reference 7 in 20 ml of acetic acid, 2.5 ml of
concentrated sulfuric acid was added and heated at 80.degree. C.
for 1 hour. After cooling, 6.8 g of potassium carbonate was added
carefully, which was diluted with water and extracted with ethyl
acetate. The extract was washed with water and with an aqueous
solution of sodium hydrogen carbonate and dried, from which the
solvent was evaporated off. Purification with a short column of
silica gel (isopropyl ether) gave 2.2 g (92.5%) of
1-(2,5-dimethoxy-3,4,6-trimethylphenyl)-1-(3-pyridyl)-1-heptene.
REFERENCE EXAMPLE 9
The heptene derivative prepared in Reference Example 8, 1.2 g (3.4
mmol), was hydrogenated in 12 ml of acetic acid in the presence of
0.6 g of 5% Pd-carbon at 80.degree. C. The reaction mixture was
analyzed with TLC. After completion of the reaction, the catalyst
was removed by filtration, and the filtrate was concentrated, to
which ethyl acetate was added and washed with a saturated aqueous
solution of sodium hydrogen carbonate. The organic phase was dried
from which the solvent was evaporated. The residue was purified
with silica gel column chromatography (isopropyl ether-hexane
(2:1)), to give 1.1 g (91.2%) of
1-(2,5-dimethoxy-3,4,6-trimethylphenyl)-1-(3-pyridyl)heptane (an
oil).
In a similar way
1-(2,5-dimethoxy-3,4,6-trimethylphenyl)-1-(3-pyridyl)propane and
1-(2,5-dimethoxy-3,4,6-trimethylphenyl)-1-(3-pyridyl)pentane were
prepared.
REFERENCE EXAMPLE 10
The solution of 525 mg (1.6 mmol) of the butanol derivative
prepared in Reference Example 5 and 0.33 ml (2.4 mmol) of
triethylamine in 3.5 ml of dichloromethane was cooled to 0.degree.
C., to which 0.15 ml (1.94 mmol) of methanesulfonyl chloride was
added with stirring. The reaction mixture was stirred at the same
temperature for 30 minutes, to which water was added and the
organic layer was separated while the water layer was extracted
with dichloromethane and the extract was combined with the organic
layer described above. The resultant organic layer was washed with
water, dried, and concentrated. The residue was dissolved in 5 ml
of dimethylsulfoxide, to which 148 mg (2.9 mmol) of sodium cyanide
was added and stirred at 80.degree. C. for 2 hours. To the reaction
mixture water was added, from which the product was extracted with
ethyl acetate. The extract was washed with water and dried, from
which the solvent was evaporated off. The residue was purified with
silica gel column chromatography, to give 445 mg (82.5%) of
4-cyano-1-(2,5-dimethoxy-3,4,6-trimethylphenyl)-1-(3-pyridyl)butane
(an oil).
In a similar way,
5-cyano-1-(2,5-dimethoxy-3,4,6-trimethylphenyl)-1-(3-pyridyl)pentane(oil),
6-cyano-1-(2,5-dimethoxy-3,4,6-trimethylphenyl)-1-(3-pyridyl)hexane
(oil) and
7-cyano-1-(2,5-dimethoxy-3,4,6-trimethylphenyl)-1-(3-pyridyl)heptane(oil)
were prepared.
REFERENCE EXAMPLE 11
To a solution of 445 mg (1.32 mmol) of the cyano derivative
prepared in Reference Example 10 in 3 ml of methanol, a solution of
1.5 g (37.5 mmol) of sodium hydroxide in 5 ml of water was added
and refluxed by heating for 3 hours. The reaction mixture was
cooled, diluted with water, neutralized with 2N hydrochloric acid,
and extracted with ethyl acetate. The extract was washed with
water, dried, and concentrated. The residue was purified with
silica gel column chromatography (CHCl.sub.3 :MeOH (9:1)), to give
400 mg (85.1%) of
5-(2,5-dimethoxy-3,4,6-trimethylphenyl)-5-(3-pyridyl)pentanoic
acid. m.p. 82.degree.-84.degree. C.
In a similar way,
6-(2,5-dimethoxy-3,4,6-trimethylphenyl)-6-(3-pyridyl)hexanoic acid
(m.p. 183.degree.-184.degree. C.),
7-(2,5-dimethoxy-3,4,6-trimethylphenyl)-7-(3-pyridyl)heptanoic acid
(an oil) and
8-(2,5-dimethyl-3,4,6-trimethylphenyl)-8-(3-pyridyl)octanoic acid
(oil) were prepared.
REFERENCE EXAMPLE 12
A solution of 5.0 g (17.8 mmol) of
2-bromo-1,4-dimethoxy-3-methylnaphthalene in 30 ml of
tetrahydrofuran was cooled to -78.degree. C., to which 11.2 ml
(17.9 mmol) of 1.6M n-butyllithium hexane solution was added
dropwise, and stirred at the same temperature for 10 minutes after
completion of the addition. Then 1.3 g (17.8 mmol) of
dimethylformamide was added dropwise to the reaction mixture, and
stirred at room temperature for 1 hour after completion of the
addition. Water was added to the reaction mixture, from which the
product was extracted with ethyl acetate. The extract was washed
with water, dried, and concentrated. The residue was purified with
silica gel column chromatography (hexane-isopropyl ether (8:2), and
crystallized from hexane-isopropyl ether, to give 2.0 g (48.9%) of
2-formyl-1,4-dimethoxy-3-methylnaphthalene. m.p.
95.degree.-96.degree. C.
REFERENCE EXAMPLE 13
A solution of 1.0 g (2.82 mmol) of the heptene derivative prepared
in Reference Example 8 in 20 ml of acetonitrile-water (1:1) was
cooled with ice, to which a solution of 4.1 g (7.48 mmol) of cerium
ammonium nitrate in 15 ml of acetonitrile-water (1:1) was added
dropwise with stirring. The mixture was stirred at the same
temperature for 30 minutes after completion of the addition, made
weakly alkaline with an aqueous solution of sodium hydrogen
carbonate, and extracted with ethyl acetate. The extract was washed
with water and dried, and the solvent was evaporated off. The
residue was separated with silica gel column chromatography
(isopropyl ether):313 mg of
(E)-1-(3,5,6-trimethylbenzoquinon-2-yl)-1-(3-pyridyl)heptene eluted
ahead, and 395 mg of (Z)-1
-(3,5,6-trimethylbenzoquinon-2-yl)-1-(3-pyridyl)heptene eluted
later were obtained.
In a similar way (E),
(Z)-7-(3,5,6-trimethylbenzoquinon-2-yl)-7-(3-pyridyl)heptenoic acid
was prepared.
The physical data of the compounds described above are shown in
Table 12.
TABLE 12
__________________________________________________________________________
Molecular formula Nuclear magnetic resonance spectrum, physical
.delta. value (ppm) in CDCl.sub.3, Formula properties TMS as
internal standard
__________________________________________________________________________
##STR26## C.sub.21 H.sub.25 NO.sub.2 oil 0.83(3H, t, J=6.0Hz),
1.30(6H, m), 1.93(3H, s), 2.00(3H, s), 2.10(3H, s), 2.20(2H, m),
5.67(1H, t, J=6.0Hz), 7.21(1H, dd, J=7.5&4.5Hz), 7.53(1H, dt,
J=7.5&1.5Hz), 8.47(2H, m) ##STR27## C.sub.21 H.sub.25 NO.sub.2
oil 0.87(3H, t, J=6.0Hz), 1.30(6H, m), 1.93(3H, s), 2.00(3H, s),
2.10(3H, s), 2.20(2H, m), 6.23(1H, t, J=6.0Hz), 7.20(1H, dd,
J=7.5&4.5Hz), 7.52(1H, dt, J=7.5&1.5Hz), 8.40(1H, dd,
J=4.5&1.5Hz), 8.47(1H, d, J=1.5Hz) ##STR28## C.sub.21 H.sub.23
NO.sub.4 oil 1.60(4H, m), 1.97(23H, s), 2.03(3H, s), 2.13(3H, s),
2.0-2.50(4H, m),5.70(0.5H, t, J=7.5Hz), 6.27(0.5H, t, J= 7.5Hz),
7.25(1H, m), 7.55(1H, m), 8.50(3H,
__________________________________________________________________________
m) *E means the isomer where the pyridine nucleus on the one carbon
and hydrogen atom on the other carbon are on the same direction in
the trisubstituted olefin bond. **Z means the isomers where they
are on the opposite directions to each other. ***E + Z means a
mixture of E and Z.
REFERENCE EXAMPLE 14
1,4-Dimethoxy-2,3,5-trimethylbenzene, 9.00 g (50 mmole), was
dissolved in CH.sub.2 Cl.sub.2 (60 ml) and stirred with
ice-cooling. After addition of 14.4 g (50.times.2.5 mmole) of
dichloromethyl methyl ether, 13.8 ml (50.times.2.5 mmole) of
titanium tetrachloride dissolved in CH.sub.2 Cl.sub.2 (30 ml) was
added dropwise over 15 minutes. After stirring for further 15
minutes with ice-cooling, the ice bath was removed and the mixture
was stirred at room temperature for 4 hours. The reaction mixture
was poured into crashed ice (about 200 g) and stirred vigorously
for 30 minutes. The CH.sub.2 Cl.sub.2 layer was washed with water
(3 times), and dried (MgSO.sub.4), from which CH.sub.2 Cl.sub.2 was
evaporated off. The residue was recrystallized from isopropyl
ether/hexane (1:1), to give 6.18 g of
2,5-dimethoxy-3,4,6-trimethylbenzaldehyde. The mother liquor was
concentrated, and the residue was purified with silica gel (60 g)
column chromatography (eluted with isopropyl ether), to give 3.70 g
of 2,5-dimethoxy-3,4,6-trimethylbenzaldehyde. Yield 9.88 g (95%),
m.p. 85.degree.-86.degree. C.
To a solution of 20 g (96 mmol) of
2,5-dimethoxy-3,4,6-trimethylbenzaldehyde in 200 ml of ethanol, 1.8
g (47.6 mmol) of sodium boronhydride was added and stirred for 30
minutes. To the reaction mixture saline was added, and the product
was extracted with ethyl acetate. The extract was washed with water
and dried, from which the solvent was evaporated off under reduced
pressure. The residue was crystallized from isopropyl ether, to
give 18.6 g (92.1%) of 2,5-dimethoxy-3,4,6-trimethylbenzylalcohol.
m.p. 121.degree.-122.degree. C.
A solution of 16.5 g (78.5 mmol) of
2,5-dimethoxy-3,4,6-trimethylbenzylalcohol in 90 ml of
tetrahydrofuran was cooled to 0.degree. C., to which 14.2 g (52.5
mmol) of phosphorus tribromide was added with stirring. After
stirring at the same temperature for 30 minutes, the reaction
mixture was diluted with water and extracted with isopropyl ether.
The extract was washed with a saturated aqueous solution of sodium
hydrogen carbonate and dried, from which the solvent was evaporated
off. The residue was crystallized from methanol, to give 17.2 g
(80.0%) of 2,5-dimethoxy-3,4,6-trimethylbenzyl bromide. m.p.
71.degree.-72.degree. C.
A solution of 15.5 g (98.1 mmol) of 3-bromopyridine in 200 ml of
ethyl ether was cooled to -78.degree. C., to which 61.3 ml (98.1
mmol) of n-butyllithium (1.6M hexane solution) was added dropwise.
For 20 minutes after completion of the addition, the mixture was
stirred at the same temperature, and then a solution of 26.8 g
(98.1 mmol) of 2,5-dimethoxy-3,4,6-trimethylbenzyl bromide in 100
ml of ethyl ether was added dropwise. After stirring at -78.degree.
C. to room temperature for 1 hour, the reaction mixture was diluted
with water and extracted with ethyl acetate. Then the extract was
extracted reversely with 2N-hydrochloric acid, and the water layer
was made weakly alkaline with a saturated aqueous solution of
sodium hydrogen carbonate and extracted with ethyl acetate. The
extract was washed with water, dried, and concentrated. The residue
was purified with silica gel column chromatography (ethyl acetate),
to give 22.8 g (85.8%) of 3-(2,5-dimethoxy-3,4,6
-trimethylbenzyl)pyridine.
In a similar way, using 2-formyl-1,4-dimethoxy-3-methylnaphthalene
as the starting substance,
3-[(2-(1,4-dimethoxy-3-methylnaphthyl)]methyl]pyridine was
synthesized via [2-(1,4-dimethoxy-3-methylnaphthyl)]methanol (m.p.
122.degree.-123.degree. C.) and
[2-(1,4-dimethoxy-3-methylnaphthyl)]methyl bromide (m.p.
79.degree.-80.degree. C.).
REFERENCE EXAMPLE 15
To a solution of 499 mg (7.33 mmol) of imidazole and 2.0 g (7.33
mmol) of 2,5-dimethoxy-3,4,6-trimethylbenzyl bromide in 12 ml of
dimethylformamide, 1.2 ml of triethylamine was added and stirred at
room temperature for 1 hour. The reaction mixture was diluted with
water and extracted with ethyl acetate. The extract was washed with
water and dried, from which the solvent was evaporated off. The
residue was purified with silica gel column chromatography
(chloroform-methanol(1:1)) and recrystallized from isopropyl ether,
to give 0.9 g (47.3%) of
1-(2,5-dimethoxy-3,4,6-trimethylbenzyl)imidazole. m.p.
82.degree.-83.degree. C.
REFERENCE EXAMPLE 16
To a stirred tetrahydrofurane solution (40 ml) of
7-(2,5-dimethoxy-3,4,6-trimethylphenyl)-7-(3-pyridyl)heptanoic acid
(3.0, 7.8 mmol) prepared in the Reference Example 11 was added
lithium aluminum hydride (450 mg, 11.9 mmol) under ice-cooling. The
reaction mixture was allowed to rise to room temperature and
stirred for 30 min. After that water was carefully added to the
reaction mixture and the product was extracted with ethylacetate.
The extract was washed with water, dried, and evaporated in vacuo
to yield
7-(2,5-dimethoxy-3,4,6-trimethylphenyl)-7-(3-pyridyl)heptanol (2.3
g, 79.6%) as, an oil, after chromatography of the crude product on
silica gel.
* * * * *